Testosterone transdermal spray with film

ABSTRACT

The invention relates to a sprayable liquid solution for the transdermal delivery of testosterone comprising testosterone, a penetration enhancer, and a film forming excipient, and to methods of treatment using this composition.

BACKGROUND

Testosterone is a primary male sex hormone that plays a key role in thedevelopment of male reproductive tissues, and secondary sexualcharacteristics such as increased muscle and bone mass. Testosteronelevels gradually decrease as men age. In addition, some younger mensuffer from primary hypogonadism, or hypogonadotropic hypogonadism,conditions in which insufficient testosterone is produced by the body.Testosterone deficiency is usually associated with adverse effects onbody composition, bone density, sexual function, and mood, and may alsoincrease cardiovascular risk. Testosterone replacement therapy may beprescribed to counteract testosterone deficiency.

Currently, testosterone replacement therapy products include atransdermal gel (Androgel®, Testim®, Fortesta®), transdermal solution(Axiron®), transdermal patch (Androderm®), injection (Delatestryl®,Aveed®) and buccal tablet (Striant®). Most of these are transdermaldosage forms, one is an injection, and one is an oral transmucosaldosage form. In addition, orally ingested tablet and capsule forms ofmethyltestosterone are available.

The oral ingestion route requires administration of a high testosteronedose due to hepatic first-pass metabolism in the liver, whileintramuscular administration is painful and can result insupra-physiological testosterone serum concentrations. Testosteronecharacteristics such as a relatively low molecular weight and moderatelipophilicity make the transdermal route the most suitable route for theadministration of testosterone.

Existing, transdermal gel and transdermal solution formulations areinconvenient dosage forms as they must be applied over large surfaceareas to achieve target plasma levels.

A more significant disadvantage of these formulations is that topicalapplication of testosterone, without a protective cover or barrier overthe area, may leave unabsorbed drug exposed creating a risk of transferof testosterone to other persons. Transfer of testosterone may causeserious side-effects in female partners and especially prepubertalchildren.

In fact, topical testosterone creams, gels and solutions are associatedwith a significant risk for secondary testosterone exposure (Lewis andGoldstein, 2009). Numerous case reports have demonstrated the occurrenceof precocious puberty or virilization in infants and young childrenfollowing contact with male parents treated with topical testosteroneproducts (Brachet et al., 2005; Bhowmick et al., 2007; Cavender et al.,2011; Franklin, 2011; Kunz et al., 2004; Martinez-Pajares et al., 2012;Nelson et al., 2013; Stephen et al., 2008; Yu et al., 1999).Virilization of adult women has also occurred following secondarytestosterone exposure from their male partners (de Ronde, 2009;Kathiresan et al., 2011; Merhi and Santoro, 2007).

Specific changes following secondary testosterone exposure in childreninclude gynecomastia, rapid growth, pubic hair, enlarged penis andclitoris and facial acne (Brachet et al., 2005; Bhowmick et al., 2007;Cavender et al., 2011; Franklin, 2011; Kunz et al., 2004; Lewis andGoldstein, 2009; Nelson et al., 2013; Yu, 1999). Adult women havereported hirsutism, clitoral enlargement, scalp alopecia, irregularmenses, deepening voice and increased muscle mass (Brachet et al., 2005;de Ronde, 2009; Kathiresan et al., 2011; Merhi and Santoro, 2007).Symptoms generally resolve after exposure to testosterone has ended,although in one case, enlarged penis persisted in a young boy (Yu,1999).

As a result of the risk of secondary testosterone exposure, AndroGel®(topical gel) and Axiron® (topical solution) are required to display thefollowing black box warning in the approved product label:

Warning: Secondary Exposure to Testosterone

-   -   Virilization has been reported in children who were secondarily        exposed to [testosterone gel/topical testosterone products].    -   Children should avoid contact with unwashed or unclothed        application sites in men using [testosterone gel/AXIRON®].    -   Healthcare providers should advise patients to strictly adhere        to recommended instructions for use.

(See First page of Prescribing Information for AndroGel® (rev. October2016) and Axiron® (rev. July 2017)).

While the case reports described above involve skin-to-skin contact,secondary testosterone exposure from contaminated clothing or bed linensmay also be possible (Mazer et al., 2005). A recent study demonstratedthe amount of residual testosterone present on the clothing of volunteersubjects using a topical testosterone solution (Axiron® [testosterone]topical solution, for topical use. Lilly USA, LLC Indianapolis, Ind.;Satonin et al., 2016). Healthy adult men (N=12) applied 1.5 mL oftestosterone 2% solution to both axillae (total testosterone dose: 120mg). After waiting>3 minutes, subjects dressed in long-sleeved cottonT-shirts. After being worn for 12 hours, the T-shirts were removed and a10 cm² sample of t-shirt was cut out from each armpit area fortestosterone quantification before and after laundering with samples ofunworn textiles. Mean testosterone in unwashed worn T-shirts was 7,603μg representing 13% of the dose to one armpit with high between-subjectvariability (3,359 μg to 13,069 μg). Mean testosterone in worn,laundered T-shirts was 260 μg representing 3% of the dose to one armpit(range, 7.55 μg to 1,343 μg). Mean transferred testosterone to othertextiles during laundering ranged from 69 μg on texturized Dacron 56TDouble to 10,402 μg on 87/13 nylon/Lycra knit, representing 0.0382% to5.78% of the dose to one armpit.

Another disadvantage of Axiron® topical solution is that the volume ofsolution applied is relatively large, and the solution can drip or run,so some of the solution may be spilled during application, resulting inan inaccurate dose. Axiron® topical solution is provided in a pumpbottle and is intended for application to the axilla (the armpit area)using an applicator. Depressing the pump once dispenses 30 mg oftestosterone. The following directions for use are provided to thepatient in the Axiron® prescribing information:

-   -   To dispense the solution, position the nozzle over the        applicator cup and carefully depress the pump fully once. Ensure        that the liquid is directed into the cup. The cup should be        filled with no more than 30 mg (1 pump actuation) of        testosterone. Dosing that requires greater than one pump        actuation must be applied in increments of 30 mg.    -   Keeping the applicator upright, patients should place it up into        the axilla and wipe steadily down and up into the axilla. If the        solution drips or runs, it can be wiped back up with the        applicator cup. The solution should not be rubbed into the skin        with fingers or hand. The process is then repeated with        application of 30 mg of testosterone (1 pump actuation) to the        other axilla to achieve a total of 60 mg of testosterone        applied. When repeat application to the same axilla is required,        the axilla should be allowed to dry completely before more        AXIRON is applied.    -   After use, the applicator should be rinsed under room        temperature, running water and then patted dry with a tissue.        The applicator and cap are then replaced on the bottle for        storage.

(See, Axiron® Prescribing Information, page 4 (rev. July 2017). Theseinstructions are fairly lengthy and complicated.

Transdermal patches may avoid transference, but have other drawbacksthat significantly reduce patient acceptance and compliance. One ofthese disadvantages is that the patch can cause skin irritation due toocclusion. Another disadvantage is that good adhesion of the patchrequires shaving of the scrotal skin.

For the various reasons described above, there is a need for an improvedtransdermal formulation of testosterone.

SUMMARY

The invention provides an improved transdermal testosterone formulation.The invention relates to a sprayable liquid solution for the transdermaldelivery of testosterone, and to a method of providing testosteronereplacement therapy by administering this composition. The compositioncontains a film forming excipient, which leaves a film on the skin. Thisfilm is washable, meaning that it can be removed with water or soap andwater. This film is a barrier that prevents transference of thetestosterone to others, such as the user's partner or child. Inaddition, the formulation provides an effective dose of testosterone ina small volume spray that is easy to apply.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and aspects of the present inventioncan be better understood from the following description of embodimentsand as illustrated in the accompanying drawings. The accompanyingdrawings, which are incorporated herein and form a part of thespecification, further serve to illustrate the principles of the presentinvention.

FIG. 1 is a graph depicting the testosterone dose recovered fromprogressive stripped layers of skin from a tape stripping studyperformed in porcine skin to compare the penetration profile of a filmforming formulation containing Eudragit® S100 to that of a non-filmforming formulation.

FIG. 2 is a graph depicting the testosterone dose recovered fromprogressive stripped layers of skin from a tape stripping studyperformed in porcine skin to evaluate the reapplication of a dose of afilm forming formulation containing testosterone and Eudragit® S100 atthe same site as a previous application of placebo film formingformulation containing Eudragit® S100.

FIG. 3 depicts an overlay of the 2DPXRD Patterns for samples taken fromsilicon wafer plates treated with formulations W, X2 or Y.

FIG. 4 is a graph depicting the cumulative water loss from water filledbottles covered with a porous membrane treated with a film formingformulation, an occluded porous membrane, or a non-occluded porousmembrane.

FIG. 5 shows the permeation profiles for testosterone recovered fromporcine skin samples treated with a film forming formulation containingEudragit® S100 with a non-film forming formulation, AXIRON®.

FIG. 6 is a graph depicting the testosterone dose recovered fromprogressive stripped layers of skin from a tape stripping studyperformed in porcine skin to compare the penetration profile of a filmforming formulation containing Eudragit® S100 with a non-film formingformulation, AXIRON®.

DETAILED DESCRIPTION

The present invention is directed to a sprayable liquid solution for thetransdermal delivery of testosterone, and to a method of providingtestosterone replacement therapy using this composition. The compositioncontains a film forming excipient that leaves a film on the skin afterthe spray has dried. This film is a barrier that prevents transferenceof the testosterone from the applied area to others, such as the user'spartner or child. This quality provides a large advantage overtestosterone topical products such as Axiron® and Androgel®. Anothersignificant advantage over these products, and over patches is that thefilm is washable, meaning that it can be removed with water or soap andwater. The film will be washed off, e.g., when showering. In otherembodiments, the film may be removed with alcohol wipes.

Yet another advantage over testosterone topical products such asAxiron®, Androgel®, or testosterone patches, is that the film left onthe skin is breathable. This characteristic may be measured using thetechnique described in Example 9 below.

The volume of spray administered in a single dose is preferably about250 or about 200 (microliters) of solution per actuation containingabout 30 mg of testosterone. In another preferred embodiment, a singledose is two actuations (sprays) each actuation delivering about 100 μLof solution containing about 15 mg of testosterone. Thus, in thisembodiment, the spray is administered twice to apply a single dose, withthe second actuation performed within a few minutes of the first. Thedesired dose of testosterone may also be divided into even smaller doseswith more than two actuations needed to deliver a total dose of, e.g.,30 mg of testosterone.

These volumes are one sixth, or less, of the volume of a single dose ofAxiron® solution (30 mg/1.5 mL/per actuation), but deliver the sameamount of testosterone. Thus, the spray of the invention is much easierto apply than Axiron® because of the reduction in volume. The lowervolume, and use of a spray pump greatly simplify application of theformulation. Although this spray is intended for application under thearm or to the upper arm, inclusion of a film forming excipient to reducethe risk of secondary testosterone exposure permits application thespray to other parts of the body e.g. shoulders. Thus, in addition tobeing safer for the user's partners and children, this product is moreconvenient to use than existing topical testosterone products.

A very thin layer of solution is formed on the skin when this spray isapplied. In only a few minutes, preferably less than 4 minutes, lessthan 3 minutes, or less than 2 minutes, the solvent/s in the sprayevaporate leaving behind a film containing testosterone. During solventevaporation, the excipients included in the spray preventrecrystallization of testosterone and maintain testosterone in anamorphous state, which is important for its penetration of the skin. Dueto this characteristic, it is possible to incorporate a highconcentration of testosterone in the formulation. Within about 5minutes, or preferably about 4 minutes or about 3 minutes, testosteroneis absorbed into the skin. The skin then acts as a reservoir from whichtestosterone is released into the systemic circulation over time. Inaddition, this film forms a barrier that significantly reduces thepotential for transference of testosterone to others, as demonstrated byan in vitro experiment described in Example 5 below.

In some embodiments, the formulation according to the invention ispackaged as a bulk solution containing multiple doses in a pump spraysystem comprising a sealed container fitted with a spray pump,preferably a metering spray pump.

Preferably, the pump system is a pump action spray. Pump action spraysrequire the application of external pressure for actuation, for example,external manual, mechanical or electrically initiated pressure.

The container holding the solution may be any suitable container for theparticular composition, such as a glass, polyethylene, aluminum or steelbottle or canister, or an aluminum pouch within a high densitypolyethylene bottle. The bottle or canister may be lined with an inertmaterial. The spray pump system may also include a dose indicator ordose counter.

The composition of the invention comprises testosterone, one or morefilm forming excipients, one or more penetration enhancers, and one ormore solvents. The composition may also contain one or more additionaloptional ingredients, such as one or more solubility enhancers, one ormore pH modifiers, one or more viscosity increasing agents and/or one ormore fragrances. For example, the composition may contain one or more pHmodifiers such as tromethamine. The concentration of the pH modifier maybe about 0.05 g/L to about 0.2 g/L. Here, grams per liter (g/L) refersto grams of organic proton acceptor per liter solvent in thecomposition. In some embodiments, the concentration of the pH modifieris about 0.05 g/L, about 0.1 g/L, or about 0.2 g/L. In some embodimentsof the invention the solvent contains Tromethamine.

The film forming excipient is an excipient, preferably a polymer, thatis soluble in aliphatic solvents, preferably in ethanol or a mixture ofethanol with other solvents. The film forming excipient is preferablyalso soluble in aqueous solutions, preferably water, and may be removedfrom skin using water or water and soap. For film forming excipientshaving pH dependent solubility, the pH of the aqueous solution must beabove or below the specific trigger pH for that excipient to dissolve.For example, some of these film forming excipients dissolve in aqueoussolutions only above, pH 6.0, only above pH 7.0, or only below pH 5.0.Therefore, soluble in water is defined herein to mean that the filmforming excipient has a solubility in water, at the pH required todissolve that excipient, that requires 30 parts or less of water(solvent) to dissolve one part of the film forming excipient (solute),or more preferably requires 10 parts of water or less to dissolve onepart of the film forming excipient. Thus, the film forming excipient hasa solubility in water, at a pH between 1 and 10, that requires 30 partsor less of water (solvent) to dissolve one part of the film formingexcipient (solute). For example, the film forming excipient has asolubility requiring 30 parts or less of water (solvent) to dissolve onepart of the film forming excipient (solute), when the pH of the water isselected from the group consisting of: below pH 5.0, above pH 4, abovepH 5, above pH 5.5, above pH 6, and above pH 7.

Preferably the film forming excipient has a solubility in ethanol thatrequires 30 parts or less of ethanol (solvent) to dissolve one part ofthe film forming excipient (solute), or more preferably requires 10parts or less of ethanol to dissolve one part of the film formingexcipient. Solubility is evaluated at room temperature.

Moreover, the film forming excipient, or mixture of film formingexcipient with other excipients such as a plasticizer or washabilityenhancer, prevents recrystallization of testosterone and maintainstestosterone in an amorphous state during and after solvent evaporation.This characteristic can be evaluated, for example, by the experimentdescribed in Example 7, or indirectly by the skin penetrationexperiments described in Examples 3 and 12.

Where the film forming excipient is a mixture of excipients, the mixtureshould have the desired characteristics.

Examples of film forming excipients that have the desiredcharacteristics include Eudragit® L100 (Methacrylic Acid and MethylMethacrylate Copolymer 1:1) (which dissolves above pH 6.0), Eudragit®S100 (Methacrylic Acid and Methyl Methacrylate Copolymer 1:2) (whichdissolves above pH 7.0), Eudragit® E100(Poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate 1:2:1) (which dissolves below pH 5.0), Hydroxypropylcellulose (Hypromellose), Ethyl Cellulose, Methyl Vinyl Ether-MaleicAnhydride Copolymers such as Gantrez® ES-435, a Butyl Ester of MethylVinyl Ether/Maleic Anhydride Copolymer; and Polyvinyl Acetate-PovidonePolymer (povidone here is a pore former/washability enhancer).

The total concentration of the one or more film forming excipients inthe composition is from about 1% w/w to about 20% w/w.

For compositions containing testosterone, when the film formingexcipient is an excipient that requires a certain pH to dissolve inwater or an aqueous environment, such as Eudragit® 5100, a washabilityenhancer can be included in the composition to make the film morewashable, i.e., easier to remove from skin with water or soap and water.In some cases, the washability enhancer also acts as a plasticizer. Apreferred washability enhancer is polyethylene glycol, preferablypolyethylene glycol 400.

The concentration of washability enhancer in the composition is about 2%to about 20% of the weight of the film forming excipient in thecomposition. Preferably it is about 8% to about 18% of the weight of thefilm forming excipient in the composition. Preferably it is about 10%,about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, orabout 18% of the weight of the film forming excipient in thecomposition.

The composition also contains one or more penetration enhancers such asAzone, Glycerol Monooleate, Isopropyl Myristate, Octisalate, Oleic Acid,and/or diethylene glycol monoethyl ether (such as Transcutol® orTranscutol® P). Octisalate and diethylene glycol monoethyl ether arepreferred.

The composition also contains one or more solvents such as Acetone,Ethanol and/or Isopropyl Alcohol. Ethanol, and mixtures of ethanol andisopropyl alcohol, are preferred.

The total solvent concentration may be around 50% w/w to about 90% w/wof the composition, but generally will make up the remainder of theweight of the composition and is a sufficient quantity to dissolve theother ingredients.

The composition may also include one or more plasticizers such asDibutyl Sebacate, Triethyl Citrate, Triacetin, Glycerol, PolyethyleneGlycol, and/or Propylene Glycol. The concentration of plasticizer in thecomposition is preferably about 2% to about 20% of the weight of thefilm forming excipient in the composition. Preferably it is about 8% toabout 18% of the weight of the film forming excipient in thecomposition. Preferably it is about 10%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, or about 18% of the weight of thefilm forming excipient in the composition. The composition of thepresent invention may also include other formulation excipients, added,e.g., to achieve a desired consistency or appearance, or to protect theformulation components from degradation and oxidation. Such excipientsinclude, for example, viscosity increasing agents, stabilizing agents,antioxidants, humectants, preservatives, colorant and fragrance agentsknown in the art of formulation.

Viscosity increasing agents that might be included in the formulationare, e.g., povidone, glycerin, hydroxypropyl cellulose, methylcellulose,and/or carboxymethylcellulose. The concentration of the viscosityincreasing agent, if included, is from about 0.5% w/w to about 3% w/w ofthe composition, preferably from about 1.0% w/w to about 2.5% w/w, andmost preferably is about 1.5% w/w.

The composition of the present invention may contain a fragrance orperfume to impart a desired aroma, or to mask odors that may beassociated with other components of the composition. If a fragrance isincluded, the concentration is from about 0.01% w/w to about 5% w/w ofthe composition, preferably from about 0.1% w/w to about 1% w/w.

Any fragrance suitable for application to the skin can be used hereinincluding a wide variety of fragrances and perfumes that are known tothose skilled in the art. The particular perfume used is largely amatter of choice, however, the fragrance should be used at a leveleffective for providing a noticeable aroma to the composition, or formasking undesired aroma of the composition. Also, the fragrance andwhatever carriers accompany it should not impart excessive stinging tothe skin, especially broken or irritated skin.

Typical fragrances are described in Arctander, Perfume and FlavourChemicals (Aroma Chemicals), Vol. I and II (1969, Allured PublishingCorporation, 1969 (ISBN 0931710375, 9780931710377), and Arctander,Perfume and Flavor Materials of Natural Origin (1994, by Allured PubCorp) (ISBN 0931710367; ISBN13: 9780931710360). Fragrance used in thepresent invention may also contain solubilizers, diluents, or solventswhich are well known in the art.

One embodiment of the invention is a composition comprising more than10% w/w testosterone; one or more penetration enhancers; one or moresolvents; and one or more film forming excipients, wherein the filmforming excipient (i) has a solubility in water, at a pH between 1 and10, that requires 30 parts or less of water to dissolve one part of thefilm forming excipient; (ii) has a solubility in ethanol that requires30 parts or less of ethanol to dissolve one part of the film formingexcipient; and (iii) can prevent recrystallization of the testosteroneand maintain the testosterone in an amorphous state during solventevaporation when the composition is applied to skin; and wherein thecomposition is a sprayable liquid solution.

In one embodiment, (i) the concentration in the composition oftestosterone is about 12% or higher, (ii) the one or more penetrationenhancers is selected from the group consisting of Azone, GlycerolMonooleate, Isopropyl Myristate, Octisalate, Oleic Acid, and diethyleneglycol monoethyl ether, (iii) the one or more solvents is selected fromthe group consisting of Acetone, Ethanol, and Isopropyl Alcohol, (iv)the one or more film forming excipients is selected from the groupconsisting of Eudragit® L100 (Methacrylic Acid and Methyl MethacrylateCopolymer 1:1), Eudragit® S100 (Methacrylic Acid and Methyl MethacrylateCopolymer 1:2), Eudragit® E100(Poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate 1:2:1), Hydroxypropyl cellulose (Hypromellose).

In another embodiment, (i) the concentration in the composition oftestosterone is about 12% or higher, (ii) the one or more penetrationenhancers is selected from the group consisting of Azone, GlycerolMonooleate, Isopropyl Myristate, Octisalate, Oleic Acid, and diethyleneglycol monoethyl ether, (iii) the one or more solvents is selected fromthe group consisting of Acetone, Ethanol, and Isopropyl Alcohol, (iv)the one or more film forming excipients is selected from the groupconsisting of Ethyl Cellulose, Butyl Ester of Methyl Vinyl Ether/MaleicAnhydride Copolymer (Gantrez® ES-435), and Polyvinyl Acetate-PovidonePolymer.

In one embodiment, the composition comprises more than 10% w/w oftestosterone. In some embodiments, the concentration of testosterone inthe composition is from about 5% w/w to about 30% w/w, or morepreferably, is from about 12% w/w to about 25% w/w. In preferredembodiments of the invention, the concentration of testosterone is fromabout 12% w/w to about 20% w/w, or from about 15% w/w to about 18% w/w.In other preferred embodiments of the invention, the concentration oftestosterone is about 12% w/w, about 15% w/w, or about 20% w/w.

In some embodiments of the invention, the concentration of the one ormore penetration enhancers in the composition is from about 1% w/w toabout 10% w/w, from about 5% w/w to about 15% w/w, from about 7% w/w toabout 12% w/w, from about 3% w/w to about 8% w/w, or preferably fromabout 4% w/w to about 7% w/w.

In some embodiments of the invention, the concentration of the one ormore solvents in the composition is from about 60% w/w to about 95% w/w,or about 50% w/w to about 90% w/w. In preferred embodiments of theinvention, the solvent is Ethanol USP in a concentration of about 60%w/w to about 75% w/w. In other preferred embodiments, the solvent is amixture of ethanol and isopropyl alcohol, and the concentration ofethanol is from about 30% w/w to about 80% w/w, or from about 40% w/w toabout 65% w/w, and the concentration of isopropyl alcohol is from about10% w/w to about 40% w/w, or from about 20% w/w to about 30% w/w.

In some embodiments of the invention, the concentration of the one ormore film forming excipients in the composition is from about 1% w/w toabout 10% w/w, or from about 3% w/w to about 8% w/w, or from about 4%w/w to about 7% w/w.

Another embodiment of the invention is a composition comprisingtestosterone, octisalate and methacrylic acid and methyl methacrylatecopolymer (1:2) (EUDRAGIT® S100), wherein the composition is a liquid.

Another embodiment of the invention is a composition comprisingtestosterone, octisalate, methacrylic acid and methyl methacrylatecopolymer (1:2) (EUDRAGIT® S100), and polyethylene glycol 400, whereinthe composition is a liquid.

Yet another embodiment of the invention is a composition comprisingtestosterone, diethylene glycol monoethyl ether, methacrylic acid andmethyl methacrylate copolymer (1:2) (EUDRAGIT® S100), and polyethyleneglycol 400, wherein the composition is a liquid.

In some embodiments of the invention, the concentration of octisalate ordiethylene glycol monoethyl ether in the composition is from about 1% toabout 15%, from about 1% w/w to about 10% w/w, from about 3% w/w toabout 8% w/w, from about 5% to about 10%, or from about 4% w/w to about7% w/w. In preferred embodiments, the concentration of octisalate isabout 4% w/w, about 5% w/w, about 6% w/w or about 7% w/w of thecomposition. In other preferred embodiments, the concentration ofdiethylene glycol monoethyl ether is from about from about 5% to about10% w/w.

In some embodiments of the invention, the concentration of methacrylicacid and methyl methacrylate copolymer (1:2) (EUDRAGIT® 5100) in thecomposition is from about 1% w/w to about 10% w/w, from about 3% w/w toabout 8% w/w, or from about 4% w/w to about 7% w/w. In preferredembodiments, the concentration of methacrylic acid and methylmethacrylate copolymer (1:2) (EUDRAGIT® 5100) is about 4% w/w, about 5%w/w, about 6% w/w or about 7% w/w of the composition.

In some embodiments of the invention, the composition comprises fromabout 12% w/w to about 20% w/w testosterone USP, from about 40% w/w toabout 65% w/w ethanol USP, from about 20% w/w to about 30% w/w isopropylalcohol USP, from about 4% w/w to about 7% w/w octisalate USP, and fromabout 4% w/w to about 7% w/w Eudragit® S100 USP/NF (methacrylic acid andmethyl methacrylate copolymer (1:2)).

In a preferred embodiment, the concentration of testosterone in thecomposition is about 12% w/w, the concentration of octisalate in thecomposition is about 6% w/w, and the concentration of methacrylic acidand methyl methacrylate copolymer (1:2) (EUDRAGIT® S100) in thecomposition is about 5% w/w.

In other embodiments of the invention, the composition comprises fromabout 12% w/w to about 25% w/w testosterone USP, from about 60% w/w toabout 75% w/w ethanol USP, from about 5% w/w to about 10% w/w diethyleneglycol monoethyl ether USP, and from about 4% w/w to about 7% w/wEudragit® S100 USP/NF (methacrylic acid and methyl methacrylatecopolymer (1:2)).

In a preferred embodiment, the concentration of testosterone in thecomposition is about 17% w/w to about 18% w/w, the concentration ofdiethylene glycol monoethyl ether in the composition is about 7% w/w toabout 10% w/w, and the concentration of methacrylic acid and methylmethacrylate copolymer (1:2) (EUDRAGIT® 5100) in the composition isabout 4% w/w to about 6% w/w.

In some preferred embodiments, the composition further comprisespolyethylene glycol 400 USP-NF in a concentration of about 8% to about18% of the weight of the film forming excipient in the composition.

The composition is a liquid at room temperature and is sprayable,meaning that the viscosity of the composition allows it to be appliedusing a spray pump at room temperature. In one embodiment, thecomposition is contained in a container comprising a spray pump withmetering valve. In one embodiment, the viscosity of the composition isless than about 50 cPs, preferably less than about 20 cPs, or less thanabout 10 cPs. Most preferably the viscosity of the composition is about4 cPs, about 5 cPs, about 6 cPs, about 7 cPs, about 8 cPs, or about 9cPs. Viscosity is measured using a viscometer such as a BrookfieldViscometer.

The invention also provides a method of increasing serum testosterone ina human male, by spraying on the skin of a human male this composition.In a preferred embodiment of this method, the amount of testosteroneadministered in a single application is about 30 mg. This amount oftestosterone can be delivered, e.g., in a single actuation of the spraycontaining 30 mg, or in two actuations each containing 15 mg, or even inmore actuations of smaller doses that add up to a total of 30 mg. Inaddition, after application of the composition, a barrier film is formedwithin about 5 minutes or less of application, and this film is capableof preventing transfer of testosterone to other persons. This can beevaluated, e.g., by the method described in Example 5. The film formedon the skin is water washable. This can be evaluated, e.g., by themethod described in Examples 6 or 10.

In some embodiments of the invention, the composition is administeredone to four times per 24 hour period. In other embodiments, thecomposition is administered one to eight times per 24 hour period. In apreferred embodiment the composition is administered four times per 24hour period. In some embodiments, a single administration can consist oftwo spray actuations, such as where each actuation delivers less than 30mg of testosterone, e.g., where each actuation delivers about 15 mg oftestosterone.

If the composition is administered more than once, it can beadministered to the same site on the skin as the previous applications.In some embodiments, it is preferred that the additional application/sof the composition is/are applied to a different site on the skin fromthe previous application/s, or that the film from the previousapplication/s is washed off the skin before the composition is appliedagain.

In one embodiment of this method the serum testosterone of the male towhich the composition is administered increases by at least 30% overbaseline.

In another embodiment, the invention provides a method of administeringthe composition to provide testosterone replacement therapy in males forconditions associated with a deficiency or absence of endogenoustestosterone, such as primary hypogonadism, or hypogonadotropichypogonadism.

In preferred embodiments, the volume of spray administered is about 500μL or less, about 400 μL or less, about 300 μL or less, about 250 μL orless, about 200 μL or less, about 150 μL or less, or about 100 μL orless. Most preferably, the volume of spray administered is about 200 uL,about 250 μL or about 100 μL. It is possible to dissolve 30 mg oftestosterone (the preferred dose) in a volume less than 250 μL of thecomposition of the invention, and achieve a testosterone concentrationof 20% w/w or higher.

As used herein, unless otherwise specified all formulation ingredientpercentages are described as percent weight by weight (% w/w), whichrefers to the weight of an ingredient as a percentage of the totalcomposition weight.

As used herein, the term “about” means±10% of the value that this termmodifies.

As used herein, the term “room temperature” refers to a comfortableambient temperature, generally taken as 20-25° C.

Several embodiments of the invention are described herein. In addition,the invention is described with reference to the following examples.This invention is not limited to the embodiments or examples describedherein. Modifications and variations may suggest themselves and areintended to be within the scope of the appended claims.

EXAMPLES Example 1: Formulations

Exemplary compositions and a manufacturing process for the testosteronespray are described below:

TABLE 1 COMPOSITIONS 1-3 Quantity per actuation Ingredient Mg % w/w Mg %w/w Mg % w/w Testosterone USP 30.00 12.00 30.00 12.00 30.00 12.00Ethanol USP 129.65 51.86 127.25 50.90 122.37 48.95 Isopropyl Alcohol USP65.85 26.34 64.00 25.60 62.50 25.00 Octisalate USP 12.50 5.00 15.00 6.0015.00 6.00 Eudragit ® S100 USP/NF 10.00 4.00 12.50 5.00 17.50 7.00(methacrylic acid and methyl methacrylate copolymer (1:2)) Polyethyleneglycol 2.00 0.8 1.25 0.5 2.63 1.05 (PEG 400) TOTAL 250.00 100.00 250.00100.00 250.00 100.00

TABLE 2 COMPOSITIONS 4-6 Quantity per actuation Ingredient Mg % w/w Mg %w/w Mg % w/w Testosterone USP 30.00 10.00 30.00 10.00 30.00 10.00Ethanol USP 159.60 53.20 156.51 52.17 150.87 50.29 Isopropyl Alcohol USP81.00 27.00 78.99 26.33 76.98 25.66 Octisalate USP 15.00 5.00 18.00 6.0018.00 6.00 Eudragit ® S100 USP/NF 12.00 4.00 15.00 5.00 21.00 7.00(methacrylic acid and methyl methacrylate copolymer (1:2)) Polyethyleneglycol 2.4 0.8 1.5 0.5 3.15 1.05 (PEG 400) TOTAL 300.00 100.00 300.00100.00 300.00 100.00

TABLE 3 COMPOSITION 7 Quantity per actuation Ingredient mg % w/wTestosterone USP 30.00 20.00 Ethanol USP 72.75 48.50 Isopropyl AlcoholUSP 30.00 20.00 Octisalate USP 9.00 6.00 Eudragit ® S100 USP/NF 7.505.00 (methacrylic acid and methyl methacrylate copolymer (1:2))Polyethylene glycol 0.75 0.5 (PEG 400) TOTAL 150.00 100.00

Manufacturing Process:

Ethanol and Isopropyl alcohol are mixed in a suitable vessel. Eudragit®S100 is added to these solvents and the mixture is stirred until a clearsolution is formed. Polyethylene glycol is added to this solution, andthe mixture is stirred for about 10 minutes. Octisalate is added and thesolution is stirred further. Testosterone is added, and the mixture isstirred until a clear solution is achieved. The solution is filled in toa suitable container and a spray pump is affixed to the container.

Example 2: Additional Formulations

Exemplary compositions and a manufacturing process for the testosteronespray are described below:

TABLE 4 COMPOSITIONS 8-10 Quantity per actuation Ingredient Mg % w/w Mg% w/w Mg % w/w Testosterone USP 30.00 12.00 30.00 12.00 30.00 12.00Ethanol USP 124.75 49.90 125.75 50.30 120.00 48.00 Isopropyl Alcohol USP60.25 24.10 63.00 25.20 60.00 24.00 Octisalate USP 12.50 5.00 15.00 6.0017.50 7.00 Eudragit ® S100 USP/NF 17.50 7.00 12.50 5.00 17.50 7.00(methacrylic acid and methyl methacrylate copolymer (1:2)) Povidone 3.751.50 2.50 1.00 3.75 1.50 Fragrance 1.25 0.50 1.25 0.50 1.25 0.50 TOTAL250.00 100.00 250.00 100.00 250.00 100.00

TABLE 5 COMPOSITIONS 11-13 Quantity per actuation Ingredient Mg % w/w Mg% w/w Mg % w/w Testosterone USP 30.00 10.00 30.00 10.00 30.00 10.00Ethanol USP 158.40 52.80 159.90 53.30 149.40 49.80 Isopropyl Alcohol USP72.60 24.20 72.60 24.20 72.60 24.20 Octisalate USP 12.00 4.00 18.00 6.0021.00 7.00 Eudragit ® S100 USP/NF 21.00 7.00 15.00 5.00 21.00 7.00(methacrylic acid and methyl methacrylate copolymer (1:2)) Povidone 4.51.50 3.00 1.00 4.5 1.50 Fragrance 1.50 0.50 1.50 0.50 1.50 0.50 TOTAL300.00 100.00 300.00 100.00 300.00 100.00

Manufacturing Process:

Ethanol and Isopropyl alcohol are mixed in a suitable vessel. Eudragit®S100 and Povidone are added to these solvents and the mixture is stirreduntil a clear solution is formed. Octisalate and Fragrance are added,and the solution is stirred further. Testosterone is added, and themixture is stirred until a clear solution is achieved. The solution isfilled in to a suitable container and a spray pump is affixed to thecontainer.

Example 3: Tape Stripping Study 1

A Tape Stripping Study was performed to compare the penetration profileof a film forming formulation containing Eudragit® S100 and PEG 400(Formulation A) to that of a non-film forming formulation (FormulationB). Formulations A and B, described in the following table, wereevaluated in this tape stripping study:

TABLE 6 Ingredients Formulation A Formulation B Ethanol USP 60.9% w/w63.0% w/w Isopropyl Alcohol USP 27.6% w/w 28.6% w/w Octisalate USP 6.0%w/w 6.0% w/w Methacrylic Acid and Methyl 5.0% w/w — MethacrylateCopolymer (1:2) USP-NF (Eudragit S100 ®) Polyethylene glycol 0.5% w/w —(PEG 400) Povidone K90 USP — 2.4% w/w TOTAL 100.0% w/w 100.0% w/wTestosterone USP 120 mg to QS 1 mL 20 mg to QS 1 mL with above solutionwith above solution

Procedure:

Porcine skin was obtained from Stellen Medical and stored in a −20° C.freezer. 100 μl of test formulation was applied to a 25 cm² area of skinsurface using a syringe and allowed to dry for 15 minutes. The skintemperature was maintained at 32° C. with a dry block heater. Ten (10)progressive layers of skin surface were removed by tape stripping asfollows. Commercial Scotch brand packaging tape was applied to the skinsurface and rubbed with lateral finger pressure for 30 seconds. The tapewas removed and extracted by shaking for 15 minutes with 20 ml ethanol.The extracted solution was analyzed by HPLC. The amounts of testosterone(% dose) recovered from each layer, as well as the remaining skin, wascalculated by comparison to a standard of known testosteroneconcentration.

The following HPLC instrument and conditions were used to analyze thesolutions extracted from the skin samples:

Instrument: Waters Acquity UPLC with PDA detector

Column: Waters Acquity BEH C18 1.7 um 2.1×50 mm

Mobile phase: 60:40 water: acetonitrile

Detection wavelength: 245 nm

Flow: 0.5 ml/min isocratic

Column temperature: 30° C.

Injection volume: 1 μl

The results of this study are described in the following table anddepicted in FIG. 1:

TABLE 7 Formulation A Formulation B % Dose % Dose % Dose standard % Dosestandard average deviation average deviation Sample n = 3 n = 3 n = 6 n= 6 Layer 1 73.5 9.3 56.0 18.6 Layer 2 7.2 3.6 11.8 4.7 Layer 3 3.2 1.05.1 1.8 Layer 4 1.3 0.5 3.0 1.2 Layer 5 1.2 0.2 2.4 1.2 Layer 6 1.0 0.72.1 1.0 Layer 7 0.9 0.4 1.3 0.7 Layer 8 0.5 0.3 1.0 0.8 Layer 9 0.5 0.41.0 0.7 Layer 10 0.5 0.5 0.7 0.3 Remaining 7.4 3.7 5.9 5.2 skin Sum 97.20.7 92.9 5.7 Sum layers 10.8 5.5 10.8 6.4 6-10 & skin

Conclusion: the penetration depth profiles of Formulations A and B arecomparable, which indicates that the film forming spray formulation hassimilar penetration characteristics as a non-film forming sprayformulation, and thus, that the film forming excipient, unexpectedly, isnot inhibiting skin penetration of the active ingredient.

Example 4: Tape Stripping Study 2

A Tape Stripping Study was performed to evaluate the reapplication of adose of a film forming formulation containing Eudragit® S100, whereinthe second application is at the same site as the previous applicationof a dose this film forming formulation.

Formulations A (Testosterone) and A (Placebo), described in thefollowing table, were evaluated in this tape stripping study:

TABLE 8 Formulation A Ingredients Formulation A Placebo Ethanol USP61.2% w/w 61.2% w/w Isopropyl Alcohol USP 27.8% w/w 27.8% w/w OctisalateUSP 6.0% w/w 6.0% w/w Methacrylic Acid and Methyl 5.0% w/w 5.0% w/wMethacrylate Copolymer (1:2) USP-NF (Eudragit ® S100) TOTAL 100.0% w/w100.0% w/w Testosterone USP 100 mg to QS 1 mL — with above solution

The Tape Stripping Procedure, and HPLC conditions described in Example 3were used for this evaluation, except that Formulation A (Placebo) wasfirst applied and allowed to dry for 15 minutes. Then Formulation A(Testosterone) was applied over the placebo and allowed to dry beforetape stripping was performed.

The results of this study are described in the following table and inFIG. 2:

TABLE 9 Formulation A Control Formulation A Reapplication % Dose % Dose% Dose % Dose % Dose % Dose Sample replicate 1 replicate 2 averagereplicate 1 replicate 2 average Layer 1 78.46 79.56 79.01 81.08 90.8985.99 Layer 2 4.11 5.74 4.93 2.43 7.96 5.19 Layer 3 1.77 2.59 2.18 1.143.33 2.23 Layer 4 1.54 1.33 1.43 0.57 0.84 0.70 Layer 5 0.69 1.57 1.130.48 1.11 0.79 Layer 6 0.32 1.02 0.67 0.23 1.13 0.68 Layer 7 0.65 0.520.59 0.23 0.40 0.32 Layer 8 0.59 0.31 0.45 0.05 0.24 0.14 Layer 9 0.260.32 0.29 0.20 0.54 0.37 Layer 10 0.18 0.22 0.20 0.04 0.14 0.09Remaining skin 7.44 5.27 6.36 2.03 2.53 2.28 Sum 96.00 98.50 97.25 88.47109.11 98.79 Sum layers 6-10 9.44 7.67 8.55 2.78 4.98 3.88 & skin

Conclusion: Application of Formulation over an existing film deliversless testosterone in deeper skin layers than the control, indicatingthat not washing off the film residue before reapplication may impactbioavailability of dose if the later application is performed at thesame site as the previous application.

Example 5: Skin Contact Transfer Study 1

A skin contact transfer study was performed to compare active ingredienttransfer from skin treated with a film forming formulation containingEudragit® S100 and polyethylene glycol 400 to transfer from skin treatedwith a non-film forming formulation.

Formulations A (Film Forming) and C (Non-Film Forming), described in thefollowing table, were evaluated in this study:

TABLE 10 Ingredients Formulation A Formulation C Ethanol USP 60.9 64.4Isopropyl Alcohol USP 27.6 29.3 Octisalate USP 6.0 6.3 Methacrylic Acidand Methyl 5.0 — Methacrylate Copolymer (1:2) USP-NF (Eudragit ® S100)PEG 400 0.5 — TOTAL 100.0% w/w 100.0% w/w Testosterone USP 120 mg to QS1 mL 120 mg to QS 1 mL with above solution with above solution

Procedure:

Vitro Skin artificial skin was obtained from IMS Inc. Artificial skinwas hydrated by incubating it overnight in 15% w/w glycerol chamberfollowed by 2 hours in 55% RH chamber. 100 ul of formulation A wasapplied to a 4×5 cm donor piece and allowed to dry for 15 minutes. 100ul of formulation C was applied to another 4×5 cm donor piece andallowed to dry for 15 minutes. The artificial skin temperature wasmaintained at 32° C. with a dry block heater. The artificial skin pieceas well as a receiver 4×8 cm piece were taped to 0.5-inch acoustic foampieces of the same size. The donor piece was placed downward facing ontop of the receiver piece. A 0.5 kg weight was placed on the donor pieceand the weighted piece slowly translated back and forth across thereceiver piece 20 times. The residue on the receiver piece wasquantitatively transferred by rinsing the receiver piece with ethanol,and the rinse liquid was then diluted to 100 ml with ethanol. Theserecovered solutions were analyzed by HPLC and the recovered amounts oftestosterone were calculated by comparison to a standard of knowntestosterone concentration.

The following HPLC instrument and conditions were used to analyze therecovered solutions:

Instrument: Waters Acquity UPLC with PDA detector

Column: Waters Acquity BEH C18 1.7 um 2.1×50 mm

Mobile phase: 60:40 water: acetonitrile

Detection wavelength: 245 nm

Flow: 0.5 ml/min isocratic

Column temperature: 30° C.

Injection volume: 1 μl

The results of this study are described in the following table:

TABLE 11 Formulation Replicate results, % transferred Formulation A 2.0,1.6 Formulation C 5.6, 5.5

Conclusion: The transfer of testosterone from the film formingformulation containing Eudragit® 5100 and polyethylene glycol 400 wassubstantially less than the transfer of testosterone from the non-filmforming formulation. This indicates that the film is effective as abarrier that limits skin to skin transfer of testosterone.

Example 6: Washability Study

A washability study was performed to compare washability from a glasssubstrate with water and with soap & water of a film forming formulationcontaining Eudragit® S100 (Formulation W), a film forming formulationcontaining Eudragit® S100 and a water-soluble component such aspolyethylene glycol 400 (Formulation Y), and a formulation containingonly testosterone (Formulation X).

Formulations W (Film Forming), Y (Film Forming with water-solublecomponent), X (Testosterone only), described in the following table,were evaluated in this study:

TABLE 12 Ingredients Formulation W Formulation X Formulation Y EthanolUSP 61.2 68.8 60.9 Isopropyl Alcohol USP 27.8 31.2 27.6 Octisalate USP6.0 — 6.0 Methacrylic Acid and Methyl 5.0 — 5.0 Methacrylate Copolymer(1:2) USP-NF (Eudragit ® S100) Polyethylene glycol — — 0.5 (PEG 400)TOTAL 100.0% w/w 100.0% w/w 100.0% w/w Testosterone USP 120 mg to QS 1mL 120 mg to QS 1 mL 120 mg to QS 1 mL with above solution with abovesolution with above solution

Procedure:

100 ul of formulation W was applied to a 4×5 cm area on a glass couponand allowed to dry for 15 minutes. The coupon was dipped in warm water.The coupon was scrubbed with a damp sponge in circular motions for 30seconds. The dipping and scrubbing steps were repeated. The coupon wasdipped in warm water and rinsed with water. The coupon was allowed todry. The procedure was repeated with formulation X and Y. The entireprocedure was then repeated with all formulations using soap & water byapplying liquid hand soap to the sponge at the beginning of the washing.Residue remaining on coupons after washing was observed to determinewhether film was washed off

The results of this study are described in the following table:

TABLE 13 Washability with Washability with Formulation Water Soap andWater Formulation W Substantial residue Substantial residue remainingremaining Formulation X Substantial residue Substantial residueremaining remaining Formulation Y No residue remaining No residueremaining

Conclusion: The film forming formulation containing Eudragit® S100,without polyethylene glycol 400, and the testosterone only formulationboth had substantial residue remaining with both water and with soap &water washing procedures indicating that the formulation residue is notwashable. The film forming formulation containing Eudragit® S100 andpolyethylene glycol 400 had no remaining residue indicating that thefilm is washable with water and with soap & water. This indicates thatthe presence of propylene glycol in the film forming formulationincreases washability of film with water and with soap & water.

Example 7: Crystallization Study

This study was performed to evaluate whether testosterone crystallizedfrom the film forming formulation following evaporation of theformulation solvent on a glass substrate, and to determine whether thefilm forming excipient or washability enhancer impact thecrystallization of testosterone. The following formulations wereevaluated.

TABLE 14 Ingredients Formulation W Formulation X2 Formulation Y EthanolUSP 61.2% w/w 64.7% w/w 60.9% w/w Isopropyl Alcohol USP 27.8% w/w 29.3%w/w 27.6% w/w Octisalate USP 6.0% w/w 6.0% w/w 6.0% w/w Methacrylic Acidand Methyl 5.0% w/w — 5.0% w/w Methacrylate Copolymer (1:2) USP-NF(Eudragit S100 ®) Polyethylene glycol 400 USP-NF — — 0.5% w/w TOTAL100.0% w/w 100.0% w/w 100.0% w/w Testosterone USP 120 mg to QS 1 mL 120mg to QS 1 mL 120 mg to QS 1 mL with above solution with above solutionwith above solution

Procedure:

A Hamilton syringe was used to spray 10 μL of each formulation onto a0.8 cm² silicon wafer plate. Each plate was then stored for 20 minutesRT (22° C.)/˜50% RH (ambient RH) before samples were taken.

Samples were collected at the edge and center of the plate using aspatula. The samples were evaluated by Two Dimensional powder X-raydiffractometry (2 DPXRD). The instrument used was a D8 Discover, Bruker2D X-ray diffractometer. Cobalt was used as the source and thecollimator setting was 800 microns beam diameter. The testosteronecrystal structures were retrieved from CSD and the obtained XRD patternswere compared with reported CSD crystal structures.

The results for each sample are shown in FIG. 3.

Conclusions: For Formulation W, evaluation by 2 DPXRD indicates that theprecipitate at the center of the sample was amorphous by 20 minutes, butthat the precipitate at the edge showed characteristic peaks ofanhydrous form. For Formulation X2, the precipitate at the center of thesample showed characteristic peaks of anhydrous form, but theprecipitate at the edge appeared to be a mixture of anhydrous andhydrate forms. For Formulation Y, the precipitate at the center and edgeof the sample were amorphous by 20 minutes.

Example 8: Additional Formulations

The following film forming compositions contain ethanol as solvent, andTranscutol® P as penetration enhancer.

TABLE 15 Composition 14 Ingredients Quantity (mg) % w/w % w/v EthanolUSP 116.40 67.75 72.30 144.60 μL (qs to 200 μL) Methacrylic acid andmethyl 8.00 4.66 4.00 methacrylate copolymer (1:2) (Eudragit ® S100)USP-NF Diethylene glycol monoethyl ether 16.00 9.31 8.00 (Transcutol ®P) USP-NF Polyethylene glycol 400 USP-NF 1.40 0.82 0.70 Testosterone USP30.00 17.46 15.00 TOTAL 171.80 100.00 100.00

TABLE 16 Composition 15 Ingredients Quantity (mg) % w/w % w/v EthanolUSP 116.48 67.81 72.35 144.70 μL (qs to 200 μL) Methacrylic acid andmethyl 8.80 5.12 4.40 methacrylate copolymer (1:2) (Eudragit ® S100)USP-NF Diethylene glycol monoethyl ether 15.00 8.73 7.50 (Transcutol ®P) USP-NF Polyethylene glycol 400 USP-NF 1.50 0.87 0.75 Testosterone USP30.00 17.47 15.00 TOTAL 171.78 100.00 100.00

TABLE 17 Composition 16 Ingredients Quantity (mg) % w/w % w/v EthanolUSP 116.89 68.08 72.60 145.20 μL (qs to 200 μL) Methacrylic acid andmethyl 7.50 4.37 3.75 methacrylate copolymer (1:2) (Eudragit ® S100)USP-NF Diethylene glycol monoethyl ether 16.50 9.61 8.25 (Transcutol ®P) USP-NF Polyethylene glycol 400 USP-NF 0.80 0.47 0.40 Testosterone USP30.00 17.47 15.00 TOTAL 171.69 100.00 100.00

Manufacturing Process:

Ethanol is added to a suitable vessel. Eudragit® S100 is added and theingredients stirred until a clear solution is formed. Next Transcutol® Pand Polyethylene glycol 400 are added and the mixture is stirred forabout 15 minutes. Finally, Testosterone is added, and the mixture isstirred until a clear solution is formed. The solution is filled into asuitable container and a spray pump is affixed to the container.

Example 9: Breathability Study

Procedure: A film forming formulation containing ethanol, testosterone,diethylene glycol monoethyl ether, methacrylic acid and methylmethacrylate copolymer (1:2) (EUDRAGIT® S100), and polyethylene glycol400, was applied to the surface of porous surgical tape (Transpore™, 3M,St. Paul, Minn.) membrane at 12.5 μl per cm² and allowed to dry. A watervapor impermeable container with an opening at the top was partiallyfilled with water. The spray was applied to the porous tape, which wasplaced over the opening of the container. The container was stored in ahumidity chamber at 37° C. in the presence of calcium chloridedesiccant, which maintained a low humidity within the chamber. Waterloss from the container over time was determined gravimetrically byperiodically measuring the container weight over a period of at least 48hours, and a water vapor transmission rate per area was determined. Tworeference control evaluations were also performed—a non-occluded controlwith only the porous tape and an occluded control in which the poroustape was covered with non-porous packaging tape.

The sample with the film forming formulation had a mean water vaportransmission rate of 1743 g/m2/24 hours, and this rate as a fractionrelative to the non-occluded control was 0.80. The relative transmissionresult is derived from the equation (sample mean rate-occluded controlmean rate)/(non-occluded control mean rate-occluded control mean rate).The results are depicted in FIG. 4.

This high water vapor transmission rate relative to the non-occludedcontrol indicates that this film forming formulation is not obstructingwater vapor transmission.

Example 10: In Vitro Film Washability Study

An in vitro study was also conducted to determine if residual drug lefton the skin once the film has been washed off.

Procedure: A film forming formulation containing ethanol, testosterone,diethylene glycol monoethyl ether, methacrylic acid and methylmethacrylate copolymer (1:2) (EUDRAGIT® S100), and polyethylene glycol400, was applied to excised porcine abdominal skin and allowed to dryfor 15 minutes. The skin was washed by wiping with a wet soft sponge for1 minute with periodic dipping in warm water and then wiped with analcohol wipe. In another experiment, the skin surface with the film waswiped only with an alcohol wipe to remove the film without washing. Anyresidual testosterone in the wipes was quantitated. Results: 5% of theapplied dose was recovered from the skin surface after washing withwater compared to 84% for an unwashed control sample where the film iswiped off with an alcohol wipe.

The ability to wash off the film off of the skin is important so thatthe patient has the option to apply the subsequent dose at the previoussite of application. In vitro testing, demonstrated that the film can bewashed off in less than a minute with water or soap and water.

Example 11: In Vitro Permeation Study

Formulation differences can impact drug bioavailability. An in vitrostudy was conducted to compare the permeation of the film formingformulation against a reference product of Axiron using Franz diffusioncells.

Procedure: Franz cells with a donor area of 4.9 cm² and 20 ml receptorchamber volume were used. The cells were assembled with excisedabdominal porcine skin and the receptor chamber was filled with 50:50ethanol: water media. The samples tested were (1) a film formingformulation containing ethanol, testosterone, diethylene glycolmonoethyl ether, methacrylic acid and methyl methacrylate copolymer(1:2) (EUDRAGIT® S100), and polyethylene glycol 400, and (2) Axiron®.The film forming formulation contained 15% w/v testosterone, and Axiron®contained 2% w/v testosterone. For each sample, 60 μl of the formulationwas added to the donor chamber of the cell. The samples were maintainedat 32° C. in an oven and the receptor chamber solution was magneticallystirred to maintain homogeneity. Samples were collected 1, 2, 4, 6, and24 hours post application.

Results: Permeation profiles indicate that testosterone from the filmforming formulation permeates at a rate that is not lower than referenceformulation Axiron. Permeation results are presented in FIG. 5.

Example 12: Tape Stripping Study

A tape stripping study was performed to compare the penetration profilesof the drug through various levels of the skin. In this study, a filmforming formulation containing ethanol, testosterone, diethylene glycolmonoethyl ether, methacrylic acid and methyl methacrylate copolymer(1:2) (EUDRAGIT® S100), and polyethylene glycol 400 (Formulation A) tothat of the Axiron® formulation (Formulation B). The results aredepicted in FIG. 6.

Procedure: Porcine skin was obtained from Stellen Medical and stored ina −20° C. freezer. 100 μl of test formulation was applied to a 25 cm²area of skin surface using a syringe and allowed to dry for 15 minutes.The skin temperature was maintained at 32° C. with a dry block heater.Ten (10) progressive layers of skin surface were removed by tapestripping as follows: Commercial Scotch brand packaging tape was appliedto the skin surface and rubbed with lateral finger pressure for 30seconds. The tape was removed and extracted by shaking for 15 minuteswith 20 ml ethanol. The extracted solution was analyzed by HPLC. Theamount of testosterone (% dose) recovered from each layer, as well as inthe remaining skin, was calculated by comparison to a standard of knowntestosterone concentration. Conclusion: The drug penetration profilesindicate that the film forming spray (Formulation A) has similar drugpenetration characteristics to that of a non-film forming solution ofAxiron® (Formulation B).

1-56. (canceled)
 57.

a) more than 10% w/w testosterone; b) one or more penetration enhancers;c) one or more solvents; and d) one or more film forming excipients, Acomposition comprising wherein the film forming excipient (i) has asolubility in water, at a pH between 1 and 10, that requires 30 parts orless of water to dissolve one part of the film forming excipient, (ii)has a solubility in ethanol that requires 30 parts or less of ethanol todissolve one part of the film forming excipient; and (iii) can preventcrystallization of the testosterone and maintain the testosterone in anamorphous state during solvent evaporation when the composition isapplied to skin; and wherein the composition is a sprayable liquidsolution.
 58. The composition of claim 57, wherein the compositionfurther comprises a washability enhancer.
 59. The composition of claim57, wherein the composition is capable of preventing transfer oftestosterone from the composition to other persons.
 60. The compositionof claim 57, wherein the composition is contained in a containercomprising a spray pump with metering valve.
 61. A compositioncomprising (a) at least about 12% w/w testosterone, (b) one or morepenetration enhancers selected from the group consisting of azone,glycerol monooleate, isopropyl myristate, octisalate, oleic acid, anddiethylene glycol monoethyl ether, (c) one or more solvents selectedfrom the group consisting of acetone, ethanol, and isopropyl alcohol,and (d) one or more film forming excipients selected from the groupconsisting of methacrylic acid and methyl methacrylate copolymer 1:1,methacrylic acid and methyl methacrylate copolymer 1:2,poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate 1:2:1, hydroxypropyl cellulose, ethyl cellulose, butylester of methyl vinyl ether/maleic anhydride copolymer, and polyvinylacetate-povidone polymer.
 62. The composition of claim 61, wherein thecomposition further comprises a washability enhancer.
 63. Thecomposition of claim 61, wherein the penetration enhancer comprisesdiethylene glycol monoethyl ether or octisalate, and wherein the filmforming excipient comprises methacrylic acid and methyl methacrylatecopolymer 1:1, or methacrylic acid and methyl methacrylate copolymer(1:2).
 64. The composition of claim 63, wherein the composition furthercomprises polyethylene glycol
 400. 65. The composition of claim 61,wherein the composition is capable of preventing transfer oftestosterone from the composition to other persons.
 66. The compositionof claim 61, wherein the composition is contained in a containercomprising a spray pump with metering valve.
 67. A compositioncomprising (a) at least 10% w/w testosterone, (b) methacrylic acid andmethyl methacrylate copolymer (1:2), (c) a washability enhancer, and (d)a penetration enhancer, wherein the composition is a sprayable liquid.68. The composition of claim 67, wherein the concentration ofmethacrylic acid and methyl methacrylate copolymer (1:2) in thecomposition is about 4% w/w to about 7% w/w, and the concentration ofpenetration enhancer is about 5% w/w to about 10% w/w.
 69. Thecomposition of claim 67, wherein the concentration of testosterone inthe composition is about 12% w/w to about 25% w/w.
 70. The compositionof claim 67, wherein the composition further comprises one or moresolvents selected from the group consisting of acetone, ethanol, andisopropyl alcohol.
 71. The composition of claim 67, wherein thecomposition further contains about 60% w/w to about 75% w/w/ethanol USP.72. The composition of claim 67, wherein the washability enhancercomprises polyethylene glycol.
 73. A method of increasing serumtestosterone in a human male, comprising spraying on the skin of thehuman male the composition of claim
 57. 74. The method of claim 73,wherein after application of the composition to the skin of the male, abarrier film is formed within about 5 minutes of the application, andwherein the film is capable of preventing transfer of testosterone toother persons.
 75. The method of claim 73, wherein the volume of sprayadministered in a single actuation is about 250 μL or less and containsat least about 15 mg of testosterone.
 76. The method of claim 73,wherein the male suffers from primary hypogonadism.
 77. The method ofclaim 73, wherein the male suffers from hypogonadotropic hypogonadism.78. A method of increasing serum testosterone in a human male,comprising spraying on the skin of the human male the composition ofclaim
 61. 79. The method of claim 78, wherein after application of thecomposition to the skin of the male, a barrier film is formed withinabout 5 minutes of the application, and wherein the film is capable ofpreventing transfer of testosterone to other persons.
 80. The method ofclaim 78, wherein the volume of spray administered in a single actuationis about 250 μL or less and contains at least about 15 mg oftestosterone.
 81. The method of claim 78, wherein the male suffers fromprimary hypogonadism.
 82. The method of claim 78, wherein the malesuffers from hypogonadotropic hypogonadism.
 83. A method of increasingserum testosterone in a human male, comprising spraying on the skin ofthe human male the composition of claim
 67. 84. The method of claim 83,wherein after application of the composition to the skin of the male, abarrier film is formed within about 5 minutes of the application, andwherein the film is capable of preventing transfer of testosterone toother persons.
 85. The method of claim 83, wherein the volume of sprayadministered in a single actuation is about 250 μL or less and containsat least about 15 mg of testosterone.
 86. The method of claim 83,wherein the male suffers from primary hypogonadism.
 87. The method ofclaim 83, wherein the male suffers from hypogonadotropic hypogonadism.88. A method of administering testosterone comprising administering thecomposition of claim 57 to provide testosterone replacement therapy inmales for conditions associated with a deficiency or absence ofendogenous testosterone.
 89. A method of administering testosteronecomprising administering the composition of claim 61 to providetestosterone replacement therapy in males for conditions associated witha deficiency or absence of endogenous testosterone.
 90. A method ofadministering testosterone comprising administering the composition ofclaim 67 to provide testosterone replacement therapy in males forconditions associated with a deficiency or absence of endogenoustestosterone.